Improved methods for achieving effective delivery of active ingredients to the desired target site remain a goal of the cosmetics, skin care and pharmaceutical industries.
A number of ways of delivering of pharmaceutically active ingredients in a controlled or slow-release manner have been developed. However, little attention has previously been paid to the fate of the carrier material once it has performed its function of delivering and releasing the active ingredient. This invention seeks to provide a new type of delivery system in which a silicon-based carrier material is converted to a beneficial substance following administration.
Topical delivery of active agents presents particular problems due to such factors as the poor stability of most biological compounds, the inability of active agents to penetrate into the deeper skin layers due to their molecular size or other adverse characteristics such as hydrophobicity, and the poor biocompatibility of topical formulations resulting in health concerns.
To enable a wider range of active ingredients to be delivered topically, considerable research has been focused on development of strategies for temporarily disrupting the stratum corneum barrier in a controllable fashion, so that drugs can permeate in sufficient and predictable quantities, thus attaining therapeutic levels. While some techniques such as iontophoresis and ultrasound have been explored as skin absorption enhancers, most effort has centred on identifying non-toxic chemical penetration enhancers that could reversibly interact with the stratum corneum in order to allow greater amounts of drug to permeate the skin. Early attempts to disrupt the barrier used simple solvents or solvent mixtures, surface-active agents and fatty acids. These materials, although capable of increasing the penetration of many chemicals across the skin, were often associated with undesirable side effects linked to their ability to extract or interact with skin components, thereby eliciting an irritation response.
The use of delivery systems has also been investigated. Commonly used delivery systems include relatively viscous fluids such as lotions, creams and gels which can be rubbed into the skin, providing immediate contact with the target region. These vehicles are frequently successfully used for both cosmetic and pharmaceutical compounds. Typically, however, they are unsuitable for delivering active compounds over long periods of time.
In order to create controlled release topical delivery system and other vehicles have been used. Particularly commonly used topical delivery systems utilise lipid based carriers, such as liposomes. However, these carrier systems have a number of drawbacks such as a potentially unstable central core and a limited loading capacity for hydrophobic compounds. They are also unsuitable for delivering substances which are too large or disruptive for phospholipid vesicles and are expensive to produce.
There remains a continuing need for improved delivery systems for topically applied active agents that can protect labile actives such as botanical extracts, desquamating enzymes and the like, and deliver such agents to the skin in active form, while being suitable for formulation into vehicles.
Silicon is an essential trace element for plants and animals. Silicon has a structural role as a constituent of the protein-glycosaminoglycans complexes found in the connective tissue's matrix of mammals, as well as a metabolic role in growth and osteogenesis (silicon favours the process of mineralisation of the bone). Thus, silicon is essential for the normal development of bones and connective tissue. Silica is also known to play an important role in skin health, acting as a collagen and elastin promoter and being involved in antioxidative processes in the body. It is implicated in the production of glycosaminoglycans and silica-dependant enzymes increase the benefits of natural tissue building processes.
For medical applications, silicon can be produced as micro- or nanoparticles, which facilitates its administration via a variety of routes such as topical, oral intake, injection or implant. Biodegradable silicon-based particles have also been used for drug targeting. However, the bioavailability of silicon is often limited by poor solubility and organic silicon-containing materials tend to exhibit unacceptably high toxicity, limiting their use in cosmetic, skin care and pharmaceutical applications.
Porous silicon was first discovered by accident in 1956 by Arthur Ulhir Jr. and Ingeborg at the Bell laboratories in US. Fabrication of porous silicon may range from its initial formation through stain-etching or anodization cell using single or poly crystal silicon immersed in hydrofluoric acid (HF) solution. Creating pores in the silicon allows both degradation of material and the loading of active compounds into pores of silicon. The use of porous silicon and porous silica as a carrier for other active compounds has been described (Nonviral gene delivery: Thinking of silica, D. Luo and W. M. Saltzman, Ahola M, Kortesuo P., Kangasniemi I., Kiesvaara J., Yli-Urpo A., Silica xerogel carrier material for controlled release of toremifen citrate. Int. J. Pharm. 195 (2000) 219-227. Ahola M., Säilynoja E. S., Raitavuo M. H., Vaahtio M. H., Salonen J. I., Yli-Urpo A U O. In vitro release of heparin from silica xerogels. Biomat. (2001) 1-8 Lu J., Liong M., Zink J. I., Tamanoi F., Mesoporous Silica Nanoparticles as a Delivery System for Hydrophobic Anticancer Drugs. Small. 2007 Jun. 13.) However, the importance of the degraded product of such carrier systems has not received full attention. In particular, sufficient attention has not previously been paid to ensuring that a silicon-containing carrier system degrades to form the beneficial and bioactive form of silicon, orthosilicic acid, without polymerisation.
The dissolution products of silicon within an aqueous environment are silicic acids. Silicic acid is a general name for a family of chemical compounds of the elements silicon, hydrogen, and oxygen, with the general formula [SiOx(OH)4-2x]n. Some simple silicic acids have been identified in very dilute aqueous solutions, such as metasilicic acid (H2SiO3), orthosilicic acid (H4SiO4, pKa1=9.84, pKa2=13.2 at 25° C.), disilicic acid (H2Si2O5), and pyrosilicic acid (H6Si2O7); and further polymerised silicic acids (PolySA), with silica (SiO2) representing the end point of complete polymerisation. The monomeric form of silicic acid, orthosilicic acid (OSA), alternatively known as monosilicic acid, and silica represent opposite sides of the silicon-based reactions with silica representing the energetically favorable form. Concentration and pH determine the direction of reaction and the equilibrium between monomers, polymers and silica:
Low Concentration/High pH High Concentration/Low pHH4SiO4←→HxSiOy←→SiO2 
Silicic acids can be considered as buffer molecules. Orthosilicic acid (OSA) is a very weak acid, weaker than, for instance, carbonic acid. It dissociates with a pK1 of 9.84 at 25° C. according to:H3SiO4−+H3O+H4SiO4+H2OH4SiO4+OH−H3SiO4−+H2O
With a pKa around 9.8 silicic acid represents a mixture of ionised and undissociated acids. The ionised species (H3SiO4−) can absorb protons from solution raising pH whereas the undissociated species can donate a proton to neutralise hydroxide ions raising pH thereby buffering the solution. It is worth noting this buffering capacity occurs quickly at low concentration. At high concentration, low pH promotes silicic acid to undergo condensation reactions producing dimers (H6Si2O7) or higher structures and water. These dimers and higher structures (SiOxOHy) can dissociate back to monomers or lower structures by absorbing hydroxide. Thereby lowering ph, Likewise these polymerised acids still dissociate at high pH neutralising hydroxide. Thus, polymerised silicic acid can also as a buffer however reactions are considerably slower.
Due to the enthalpy of the dimerisation reaction and subsequent polymerisation reactions at ambient temperatures under biological pH polymerisation generally proceedsH4SiO4→2H2O+SiO2 Via H4SiO4+H4SiO4→H2O+H6Si2O7[SinOm]—OH+H4SiO4→[Sin+1Om+2]—OH+2H2O
The back reaction is of course possible but is thermodynamically unfavourable requiring pH>13 and heat to return from SiO2 to H4SiO4.
The reaction of OSA with itself to form silica can be limited by reducing its concentration to the point where two OSA molecules meeting is as likely as a dimer meeting an OH− ion and dissociating. The concentration in limit of a pure solution containing only silicic acid is around 10−4 Mol·L−1 (Studies of the kinetics of the precipitation of uniform silica particles through the hydrolysis and condensation of silicon alkoxides, Journal of Colloid and Interface Science, Volume 142, Issue 1, 1 March 1991, Pages 1-18 G. H Bogush and C. F Zukoski IV) and above this concentration one cannot extract pure OSA as other PolySA species are formed. At higher concentrations, however, orthosilicic acid can be prevented from polymerisation through the addition of other chemical species and method of formulation discussed below.
Kinetics of Dissolution:

The kinetics of dissolution, ignoring surface area, are dependant on the pH and the availability of reactive species. The main reactive species in the dissolution process is water in its protonated and deprotonated forms. Kinetic data for the rates of reaction in both directions, see Brinker sol-gel science and technology. However the addition of other molecules can create side reactions greatly shifting the equilibrium up to silicic acid or right to silicon oxide (glass) depending on their pKa value this will be discussed further in the particle environment section.
The control of dissolution through adjustment of pH is possible for storage applications, however pH in vivo is tightly controlled by the body. Thus adjustment of dissolution rates through particle size and surface chemistry must be tailored prior to in vivo use. Thus, to increase the rate of dissolution pure, protonated or hydroxylated silicon is preferable. To slow the dissolution of silicon particles a suitable oxide layer thickness will produce a lag in the dissolution profile whilst the oxide layer slowly dissolves. the thickness of this oxide layer will determine the length of the lag period before any water has access to the silicon core.
Care will have to be taken with the manipulation of the silicon surface as binding of drug molecule will be highly dependant on the surface energy. Hydroxylation of the surface will reduce contact angle favouring the binding of polar molecules. Whilst the growth of a surface oxide will increase contact angle favouring the binding of hydrophobic molecules. Thus a combined strategy of size and surface chemistry will be required to obtain control over the level of drug loading and dissolution rate.
The use of silicon oxides in various forms has been proposed as a nutrient for skin and other parts of the human body, such as nails or bones, and in the treatment of bone or joint conditions such as arthritis. The prerequisites for biologically active silicon are its aqueous solubility and its subsequent reactivity towards biomolecules. Silica hydrosolubility depends on the ratio of free OH groups (silanol functional groups) to silicon backbone. Increasing silica complexity results in a reduced ratio of silicon to silanol groups resulting in large macro molecules of poor solubility and reactivity compared to smaller analogues. Thus, the effectiveness of such formulations depends on the ability of silicon to degrade to form OSA, the most biologically active and hence beneficial type of silicic acid. It has been shown that OSA has a high affinity for Al3+ ions and enhances their elimination. It can therefore act against the toxic effects of aluminium on bones and brain, especially in neurologic degenerative diseases such as Alzheimer's disease. Formation of metal ion silicic acid salt complexes stabilise OSA in the monomeric form and aid elimination of potentially harmful metal ions from the body.
OSA is a very weak acid which is unstable stable at pH levels lower than 9.5 and quickly precipitates or forms sols or gels which are not very bioavailable for the human body. It is therefore very difficult to prepare highly concentrated (>0.5% silicon) solutions of orthosilicic acid and oligomers. Furthermore, the type of silicic acid produced by a formulation is largely determined by the concentration of silicic acids silicon compounds and the pH of the media in which this dissolution occurs. In order to obtain OSA in vivo, the silicic acid concentration must be tightly controlled.
Although others have considered the potential use of microparticles of silicon-based materials as delivery vehicle for beneficial compounds, the production of high and controlled levels of degraded silicon—especially its bioactive form, ortho silicic acid (OSA) following the degradation of such carrier systems remains difficult to achieve. Previously proposed silicon-based drug delivery systems do not produce and release OSA in a controlled manner and the extent to which the silicic acid remains in the form of OSA has not previously been determined for those formulations. Since many formulations decompose rapidly producing high concentrations of OSA, this could possibly lead to inadvertent poly silicic acid (PolySA) production.
While silica and silicon-based formulation have been used as a carrier system for several applications, polymerisation is a major safety issue if silicon is used as a drug carrier. Previously disclosed delivery systems using all forms of silicon, whether porous, microsilica, nanosilica or silicon dioxide particles, are claimed to undergo dissolution with the particles being degraded to form silicic acid. However, a major problem with known silicon-based delivery systems is that the production and release of OSA is not controllable and, as a result, polymerisation may occur. The particle size distribution of precipitated Si is not homogenous and the silicon structure consists of aggregates and agglomerates. Primary particles of silicon, or silica, become coupled to each other by hydrogen bonds at first into primary agglomerates (aggregates) which, at a further stage, bind to form spatial structures of the secondary agglomerates. This lack of homogeneity of unmodified silica and the particle size growth can be a significant safety issue if the particles are still in the body in the form of silicon particles or silicic acid while releasing the active compounds.
Skincare, cosmetic, pharmaceutical and cosmeceutic compositions comprising stabilised OSA are known. However, such stabilised compositions are not suitable for use as drug delivery systems. For example, the use of bioavailable orthosilicic acid in skin care compositions has been described previously in the literature by Barel et al. (2004): Effect of oral intake of choline-stabilized orthosilicic acid on skin, nails and hair in women with photo-damaged facial skin, Skin Research and Technology, 10:1 and Barel et al. (2005): Effect of oral intake of choline-stabilized orthosilicic acid on skin, nails and hair in women with photo-damaged facial skin, The Journal of the Academy of Dermatology, Suppl., 3 (52): 28.
The production of OSA outside the body has been studied and the supply of the body with pre-produced OSA solution has been described in JP 58-176115. Concentrated solutions of orthosilicic acid have been produced in which orthosilicic acid is stabilised by a very acid pH that prevents polymerisation by hydrolysing the siloxane bonds Si—O—Si. As the orthosilicic acid is in solution form and not solid or semi-solid particles, it is not able to deliver the active compound in a controlled manner.
Australian patent AU 774668 B2 describes a complex containing biologically assimilable orthosilicic acid in a solid form that is stabilised by complexation to a polypeptide. Such complexes are prepared by hydrolysing a precursor of hydrosilicic acid, such as tetraalkoxysilane, in the presence of an aqueous solution of the polypeptide and then evaporating the water to form a sold complex. Suitable polypeptide stabilizers described in AU 774668, which are capable of stabilising orthosilicic acid, include protein hydrolysates, collagen hydrosylates. Although such complexes are capable of delivering OSA in a biologically assimilatable form that is stable at neutral and physiological pH levels, it does not provide a system that is capable of delivering other beneficial compounds, such as therapeutically active agents.
U.S. Pat. No. 5,922,360 describes stabilized forms of OSA and biological preparations comprising stabilised OSA. In particular U.S. Pat. No. 5,922,360 describes stabilization using a stabilizing agent containing a nitrogen atom with a free electron pair which forms a complex with the silanol groups of the OSA. Suitable stabilizing agents described are quaternary ammonium compounds, for instance tetra-alkyl compounds, wherein each alkyl group contains for instance 1-5 carbon atoms, in particular methyl and ethyl groups, and trialkylhydroxyalkyl compounds, wherein the hydroxy group is preferably methanol or ethanol. Choline, for example in the form of choline hydrochloride, is described as particularly suitable and also an amino acid, such as proline and serine which enhances uptake in the stomach and gives additional stability. The stabilised OSA is prepared by hydrolysing a silicon-containing compounds in water in the presence of the stabilising agent so that OSA complexes with the stabilising agent upon production. International patent application WO 2004/016551 A1 similarly discloses a method for preparing a silicic acid containing extrudate in which a silicon compound is hydrolysed to OSA in the presence of a stabilising agent selected from a quaternary ammonium compound, an amino acid or an amino acid source.
There remains a need for a silicon-based delivery system in which the silicon-containing carrier material reliably degrades to OSA and in which polymerisation of the OSA can be prevented.